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Background: The number of published randomized clinical trials (RCTs) using targeted maintenance therapy for newly diagnosed epithelial ovarian cancer is increasing. Our objective was to evaluate the comparative effectiveness of each maintenance therapy using a network meta-analysis. Materials and methods: A systematic search for RCTs was conducted using Medline, Embase, and CENTRAL databases followed by a Bayesian network meta-analysis. The primary outcome was progression-free survival (PFS) and the secondary outcome was overall survival (OS). Pooled hazard ratios (HRs) with 95% credible intervals (95% CrIs) were used to estimate outcomes. Results: A total of 11 RCTs involving 6631 patients were included. Network meta-analysis showed that pure maintenance therapy with pazopanib resulted in a significantly better PFS compared with placebo (HR, 0.77; 95% CrI, 0.65-0.92). Bevacizumab-throughout treatment was also associated with a better PFS (HR, 0.76, 95% CrI, 0.69-0.84). However, anti-CA-125 monoclonal antibodies (abagovomab and oregovomab) showed no significant survival benefit. Moreover, combined analysis showed that targeted-throughout was not significantly superior to pure targeted maintenance therapy for PFS and OS. Stratified analysis showed paralleled results with no significant difference between pazopanib pure maintenance and bevacizumab-throughout treatments. Conclusion: Our study showed a survival advantage conferred by pazopanib and bevacizumab as maintenance therapy in newly diagnosed epithelial ovarian cancer. Further clinical trials are essential to both determine the effect of bevacizumab in the maintenance stage and identify the specific subgroup(s) that benefit.

CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy. Cancer Res; 75(22); 4669–74. ©2015 AACR.

To determine whether abagovomab induces protective immune responses in ovarian cancer patients in first clinical remission. The present analysis is a substudy of monoclonal antibody immunotherapy for malignancies of the ovary by subcutaneous abagovomab trial (NCT00418574). The study included 129 patients, 91 in the abagovomab arm and 38 in the placebo arm. Circulating CA125-specific cytotoxic T lymphocytes (CTL) were measured by a flow cytometry-based interferon-γ producing assay. Human antimouse antibody and anti-anti-idiotypic (Ab3) were assessed by ELISA. Patients were evaluated before starting the treatment and at different time points during induction and maintenance phases. A similar percentage of patients in both the placebo and abagovomab arms had CA125-specific CTL (26.3 and 31.8 %, respectively; p = 0.673 by Fisher’s exact test). Patients with CA125-specific CTL in both arms tended to have an increased relapse-free survival (RFS, log-rank test p = 0.095) compared to patients without. Patients (n = 27) in the abagovomab arm without CA125-specific CTL but that developed Ab3 above the cutoff (defined as median Ab3 level at week 22) had a prolonged RFS compared to patients (n = 24) that did not develop Ab3 above the cutoff (log-rank test p = 0.019). Abagovomab does not induce CA125-specific CTL. However, patients with CA125-specific CTL perform better than patients without, irrespective of abagovomab treatment. Abagovomab-induced Ab3 associate with prolonged RFS in patients without CA125-specific CTL. Further studies are needed to confirm these data and to assess the potential utility of these immunological findings as a tool for patient selection in clinical trial.

Introduction Despite encouraging phase I and II study results, vaccination of ovarian cancer patients with abagovomab – an anti-idiotypic mAb that mimics the ovarian cancer CA125 protein – failed to demonstrate efficacy in the phase III trial named MIMOSA (NCT00418574). We postulated that in this trial patients with a more robust immune system did respond to abagovomab but went undetected among a larger number of non-responders. We also postulated that assessment of the immune system status ahead of abagovomab administration might predict patients’ propensity to respond to abagovomab. Materials and methods The immune system status was assessed as percentage and absolute count of CD8+ T cells producing IFN-γ after stimulation with Staphylococcal Enterotoxin B (SEB) in 80 patients on abagovomab and 31 patients on placebo from the MIMOSA trial ahead of treatment. Optimal cutoffs of the two variables were calculated by the web application “Cutoff Finder” as the points with most significant (log-rank test) splits based on relapse-free survival (RFS). The Kaplan–Meier curves and log-rank test served to estimate and compare RFS in patients with percentage and absolute count of IFN-γ producing CD8+ T cells around the cutoffs. Results Patients on abagovomab with IFN-γ producing CD8+T cell percentage above the cutoff had a better RFS (p = 0.042) than those with IFN-γ producing CD8+T cell percentage below the cutoff. Patients on abagovomab with IFN-γ producing CD8+T cell absolute count above the cutoff had a better RFS (p = 0.019) than those with IFN-γ producing CD8+T cell absolute counts below the cutoff. Consistently, the RFS of patients on abagovomab with IFN-γ producing CD8+T cell percentage and absolute counts values below the respective cutoffs was identical to that of patients on placebo. Neither the percentage nor the absolute count of IFN-γ producing CD8+T cells correlated with RFS in patients on placebo. Conclusions A robust immune system is essential to obtain a clinical response in OC patients undergoing abagovomab immunotherapy whereas a robust immune system does not confer per se a survival advantage. Further work will clarify whether the results shown here apply only in the present setting or extend to other types of cancer and/or immunotherapeutic agents.

This study evaluates the stability of lyophilised aluminium hydroxide adjuvanted vaccine formulations during stress testings at elevated temperatures. Trehalose, dextran, HES, PVP, saccharose and sorbitol were used as excipients to protect both vaccine components – protein/antigen and an adjuvant – during lyophilisation from freezing- and dehydration stresses. Exemplary vaccine components were abagovomab, a monoclonal anti idiotypic antibody developed as an immuno-vaccine for the treatment of ovarian cancer and aluminium hydroxide adjuvant. All six excipients protected the monoclonal antibody abagovomab from denaturation and loss in potency as detected with sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE). Enzyme-linked immunosorbent assay (ELISA) could show maintenance of abagovomab potency within the lyophilised samples throughout the stress testings as could also be shown for stress tested drug substance. Particle size analysis, sedimentation assay and wide angle X-ray diffraction (WAXD) revealed that dextran, hydroxyethyl starch (HES) and polyvinyl pyrrolidone K 25 (PVP) particularly enhanced stability of the adjuvant within a vaccine formulation during stress testing. The present study could further demonstrate the applicability of Nile Red fluorescence microscopy and adsorption studies for in-depth characterisation of freeze dried vaccine formulations.

Background: Abagovomab is a murine anti-idiotypic antibody against the antigen CA-125 which has been shown to elicit humoral and cellular immune responses against ovarian cancer (oc). Patients and methods: This phase I trial included 36 patients with recurrent oc comparing two subcutaneous (s.c.) vaccination schedules: nine (group L) versus six injections (group S), 18 patients in each group. Four injections of 2.0 mg abagovomab were administered every 2 weeks and then two or five additional doses monthly. Primary endpoint was drop-out rate due to toxicity, and the secondary endpoint was analysis of immunological response. Results: Treatment was completed in eight (44%) and 16 (89%) patients in groups L and S, respectively. Premature termination occurred due to patient withdrawal or disease progression. No treatment-limiting toxicities occurred in either group. The most common toxicity related to the vaccine was grade 1/2 local injection site reaction. Induction of Ab3 was observed in all evaluable patients. There were no differences between the groups with regard to induction of human anti-mouse antibody (P = 0.1006). IFNγ-expressing CA125-specific CD8+ T-cells were significantly more frequent in group L, while there was no significant difference between CD4+ T-cells in the two groups. Conclusions: Abagovomab s.c. vaccination is safe and well tolerated. The long vaccination schedule tended to be more effective with regard to AB3-induction and cellular cytotoxicity.

Purpose: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer.Experimental Design: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response.Results: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade >2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P = 0.6268), dose (P = 0.4602), or cohort (P = 0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL).Conclusions: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.

Purpose: A Phase I/IIb multicenter study was conducted to evaluate the safety and immunogenicity of the anti-idiotypic antibody vaccine ACA125 that functionally imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma. A preliminary report on the initial 42 patients demonstrated safety and immunogenicity. Experimental Design: Using the complete intention-to-treat population (n = 119) who received a mean of 9.7 ACA125 applications, survival was analyzed with respect to immunological responses. Results: In 81 patients (68.1%), a specific anti-anti-idiotypic antibody (Ab3) response could be induced. Additionally, the development of CA125-specific antibodies (Ab1′) and antibody-dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed in 50.4% and 26.9% of patients, respectively. The median survival of all patients was 19.4 months (range, 0.5–56.1 months). Ab3-positive patients showed a significantly longer survival (median, 23.4 months; P < 0.0001) as compared with Ab3-negative patients (median, 4.9 months). A positive Ab3 response remained associated with longer survival when controlling for other prognostic factors including FIGO (International Federation of Gynecologists and Obstetricians) stage, response to and type of first-line chemotherapy, number of previous treatments, or concomitant antitumor therapy. With regard to safety, repeated vaccination was well tolerated. No serious adverse events related to the application of ACA125 occurred. Conclusions: Although the uncontrolled design of this study prevents definitive conclusions with respect to subgroups, the data support a relationship between Ab3 response and survival time. Thus, the need for further randomized, controlled clinical trials to establish efficacy of the vaccine ACA125 seems to be indicated.

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM x anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens.

Purpose To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission. Patients and Methods Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response. Results Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti–anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response. Conclusion Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.

Ovarialkarzinome sind die häufigste Todesursache durch gynäkologische Malignome in den USA und Deutschland. Aufgrund der Symptomarmut zu Beginn der Erkrankung sowie das Fehlen sufizienter Frühscreeningsmethoden werden über 70% der Ovarialkarzinome in einem fortgeschrittenen Stadium diagnostiziert. Trotz einer insgesamt positiven Entwicklung der heutigen Therapieregime bleibt festzustellen dass fortgeschrittene Stadien mit einer sehr schlechten Prognose assoziiert sind, wobei die meisten Patientinnen trotz optimaler Behandlung (OP mit anschließender Polychemotherapie) bald danach ein Rezidiv erleiden. Aus diesem Grunde erscheint die Ergänzung der konventionellen Therapie als durchaus sinnvoll. Die Immunisierung mit anti-idiotypischen Antikörpern stellt eine interessante Zusatzstrategie in der Behandlung des Ovarialkarzinoms dar. Dabei können anti-idiotypische Antikörpern in ihren variablen Domänen Tumor-assoziierte Antigene imitieren. Durch die Präsentation von Tumor Antigenen in eine fremde molekulare Umgebung ist es möglich, eine spezifische Immunantwort gegen an sich nicht oder nur schwach immunogene Tumor-assoziierten Antigenen und im Endeffekt gegen die Tumorzelle selbst zu erzeugen. Anti-Idiotypen wurden in der Immuntherapie vielfältiger Tumore eingesetzt, wobei die Wirksamkeit einiger dieser Antikörpern bereits in klinische Phase III Studien untersucht wird. Hierzu zählen: Kleinzelliges Lungenkarzinom, Kolorektales Karzinom, Ovarialkarzinom, B-Zell Lymphom und malignes Melanom. Abagovomab (=ACA125) ist ein muriner anti-idiotypischer Antikörper der das tumorassozierte Antigen CA125 funktionell imitiert und aktuell in einer internationalen Phase II/III Studie (MIMOSA/AGO-Ovar10) in der Therapie des fortgeschrittenen Ovarialkarzinoms eingesetzt wird. CA125 ist ein Tumor Antigen welches von der Mehrzahl der Ovarialkarzinome überexprimiert wird, wobei die meisten Patientinnen gegenüber diesem Antigen tolerant sind. Allerdings kann diese Immuntoleranz durch ein stellvertretendes CA125 Antigen wie Abagovomab überwunden werden. Bereits mehrere klinische Studien ergaben deutliche Hinweise auf die therapeutische Wirksamkeit von Abagovomab mit verbesserten klinischen Ansprechraten sowie verlängerten Überlebenszeiten. Ein Nachteil vieler anti-Idiotypen Vakzine scheint ihre geringe Immunogenität zu sein, so dass zur Erhaltung einer spezifischen anti-tumoralen Immunantwort Mehrfachapplikationen mit hohen Antikörperdosen notwendig sind, was Gefahren wie Effektivitätsverlust, Toleranzinduktion und Allergisierung nach sich ziehen könnte. Im Hinblick auf die Gentherapie des Ovarialkarzinoms mittels anti-Idiotypen, wurde im Rahmen einer Vorarbeit der humanisierten Abagovomab Abkömmling ACA125hFc hergestellt, welcher im Unterschied zum murinen Ursprungsantikörper mit einer humanen konstanten Fc Region ausgestattet war. Die Intention dabei war, die Induktion unspezifischer anti-Maus Antikörper im humanen System zu reduzieren, welche infolge der Immunisierung mit dem murinen Abagovomab beobachtet wurden und die spezifische anti-tumorale Immunantwort teilweise überlagerten. Im Rahmen derselbigen Vorarbeit wurde ein kontinuierliches in vitro Freisetzungssystems für den anti-Idiotypen ACA12hFc mittels Bioverkapslungstechnologien hergestellt, mit dem Ziel eine dauerhafte spezifische Immunantwort gegen das Tumor Antigen CA125 zu erzeugen. Das Prinzip der Bioverkapslung beruht auf die physikalische Immunisolation non-autologer Zellen mittels einer semipermeablen Membran, welche als immunologische Schutzbarriere fungiert und so im Gegensatz zu herkömmlichen Transplantationsmethoden auch ohne Immunsupression funktioniert. Die verkapselten Zellen gestalten sich wie kleine Bioreaktoren: über Membrandiffusion erfolgt ein bidirektionaler, kontinuierlicher Austausch kleiner Moleküle wie Nährstoffe, Sauerstoff, rekombinante Proteine etc. zwischen Spender und Empfänger, wobei große Moleküle und Zellen die Membran nicht passieren können. Es ist durchaus vorstellbar, dass ein Depotsystem welches die kontinuierliche anti-Idiotypen Expression sicherstellt, in der Lage ist dessen Immunogenität zu verbessern um schließlich eine dauerhafte Tumorregression zu induzieren. Zu diesem Zweck wurden murine rekombinante C2C12 Myoblasten welche den ACA12hFc Antikörper stabil exprimierten, in dafür eigens hergestellte Makrokapseln eingebracht und in vitro untersucht. Aus den Ergebnissen dieser Vorversuche resultierte, dass beide getesteten Kapseltypen (PES vs. PVDF) bis Versuchsende (=1 Jahr) die Voraussetzungen für ein kontinuierliches in vitro ACA125hFc-Freisetzungssystem erfüllten. Im Rahmen der aktuellen Arbeit wurde anhand eines non-autologen Mausmodells überprüft, inwiefern das in vitro entwickelte ACA125hFc Biokapselsystem, einen Vorteil gegenüber der herkömmlichen Vakzinierung nach sich zieht und somit in vivo in der Lage ist die Immunogenität von anti-Idiotypen zu verbessern. Zu diesem Zweck wurden rekombinante C2C12 Myoblasten in zwei chemisch unterschiedlichen Kapseltypen eingebettet (PES bzw. PVDF) mit dem Hintergrund auch mögliche Unverträglichkeiten durch den Einsatz von z.B. unterschiedlichen Materialien zu erfassen. Anschließend erfolgte die Implantation der Biokapseln in ein allogenes Mausmodell (Balb/c), wobei die humorale Immunität mittels ELISA Techniken bzw. die zelluläre Immunantwort mittels Durchflußzytometrie untersucht wurde. Dabei konnte gezeigt werden, dass die Immunogenität des anti-idiotypischen Antikörpers ACA125hFc welcher das CA125 Tumor Antigen funktionell imitiert, mittels Bioverkapselungstechnologien deutlich gesteigert werden kann. Die Überlegenheit der kontinuierlichen in vivo Freisetzung kleiner ACA125hFc Mengen aus verkapselten Myoblasten gegenüber der herkömmlichen Vakzinierug mit hohen anti-Idiotypen Dosen konnte hierbei anhand der Analyse von CA125 spezifischen Immunantwort eindrucksvoll demonstriert werden: über die herkömmliche anti-Idiotypen Vakzinierung konnte keine spezifische zelluläre Immunantwort induziert werden. Hingegen erfolgte über die konstante endogene Freisetzung von ACA125hFc Antikörpern aus Kapselimplantaten eine eindeutige CA125 spezifische T Zellantwort sowohl in Form von T Helferzellen als auch als zytotoxischen T Zellen. Auch die hierbei induzierte spezifische humorale Immunantwort (= anti-anti ACA125hFc Antikörper) war bei der herkömmlichen Immunisierung deutlich schwächer ausgeprägt als bei den Kapselimplantaten. Aus den obigen Ergebnissen resultierete, dass beide untersuchten Biokapseln (PVDF vs. PES) erfolgreich als allogene Implantate zur kontinuierlichen endogenen Sekretion von ACA125hFc Antikörpern bestehen konnten. Da beide Kapseltypen trotz einiger Unterschiede in den Membraneigenschaften (Porengröße bzw. Material) ähnlich gut verträglich waren und nach Explantation eine exzellente Zellvitalität ohne Anzeichen von Implantatabstoßung zeigten, können letztendlich auch beide als gleichwertige Immunisolatoren für allogene Zellen befunden werden. Lediglich in der Induktion einer spezifischen humoralen Immunantwort gab es Unterschiede: PES Biokapseln wiesen höhere spezifische anti-ACA125hFc Antikörpertiter vergleichbar mit den PVDF Kapseln, was wahrscheinlich auf die größeren PES Membranporen zurückzuführen war. Allerdings schien dieser Effekt bei der Induktion einer zellulären Immunität keine Rolle mehr zu spielen, da beide Kapseltypen vergleichbar hohe CA125 spezifische T Zellantworten lieferten. PVDF Kapseln waren hingegen mechanisch stabiler, was für die Implantatsicherheit bzw. Handhabung von großem Vorteil sein könnte. Nachfolgende Untersuchungen (z.B. Tumortiermodell) sollen darüber Aufschluss geben inwiefern die verbesserten immunologischen Eigenschaften von bioverkaspelten anti-Idiotypen letztendlich auch zu einer dauerhaften Tumorregression führen können, was bislang durch herkömmliche Vakzinierungsstrategien leider nicht erzielt werden konnte. Ausserdem sollte untersucht werden inwiefern dieses neue ACA125hFc Freisetzungsmodell auch auf andere anti-Idiotypen übertragbar ist bzw. inwieweit hierbei eine verbesserte spezifische anti-tumorale Immunantwort möglich ist., Ovarian cancer represents the third most common malignancy of the genital tract. Because more than 50% of ovarian cancer patients are stage III and 20 % are stage IV at the time of diagnosis, this tumour is associated with an extremely unfavourable prognosis. Because the success of chemotherapy regiments after failure of first-line therapy is limited, the development of other therapeutically methods e.g. immunotherapy became necessary. One promising application in ovarian cancer immunotherapy is the administration of the murine anti-idiotypic antibody abagovomab that imitates the tumour-associated antigen CA 125, which is overexpressed by about 80 % of ovarian carcinomas. Abagovomab is currently being tested in a Phase II/III trial in ovarian cancer patients with a complete response after standard first-line chemotherapy. Activating the cancer hosts immune system via an anti-idiotypic network system is a new strategy that is worth being pursued in the fight against ovarian cancer. A drawback of abagovomab is its low immunogenicity. The goal of the present work was to determine if a continuous delivery system for abagovomab will show an advantage over conventional immunization in inducing a durable antitumor response. Based on bioencapsulation technologies, we generated in a previous work a cell culture system that acts as a continuous delivery system for the abagovomab derivative ACA125hFc and concluded that recombinant C2C12 myoblasts encapsulated in semi permeable hollow fibers can be employed as secretion devices for this antibody. In the present work we developed an allogene mouse model, acting as a long term delivery system for ACA125hFc expressing allografts. Compared with conventional anti-idiotypic immunization the new antibody application systems showed a significant improvement in humoral as well as in cellular immune responses. Further studies using e.g. ovarian cancer animal models will show if this new delivery system is able to improve the anti-tumoral response against CA125.

Investigations for the physiological role of regulatory T-cells in female patients with advanced Ovarialkarzinom after immune therapy with anti-idiotyp Abagovomab, Aufgrund aktueller Publikationen wurde postuliert, dass das immunologische Ansprechen auf die Abagovomab-Therapie in Form einer CA125-spezifischen T-Zellresponse durch körpereigene immunsuppressive Mechanismen limitiert werden könnte. Aus diesem Grund wurde zum einen die Frequenz immunsuppressiver Tregs im Verlauf der Therapie bestimmt, zum anderen das suppressive Potential von CTLA-4 anhand einer selektiven Blockade mit anti-CTLA-4 Antikörper in vitro untersucht. Ziel war es festzustellen, ob ein zusätzliches Management immunsuppressiver Mechanismen eine Steigerung des immunologischen Ansprechens bewirken könnte und somit eine mögliche Option für weiterführende Studien mit Abagovomab darstellen könnte. Es konnte festgestellt werden, dass es keinen Unterschied der Treg-Frequenzen im Vergleich zu Normalpersonen gab. Im Verlauf der Vakzinierung konnte zwar bei 7 der 12 untersuchten Patientinnen eine Tendenz zu höheren Treg-Frequenzen nach 5/6 Immunisierungen gemessen werden, eine signifikante Korrelation zur Phase der Immunisierung oder einer CA125-spezifischen T-Zellresponse konnte jedoch im Gesamtkollektiv nicht festgestellt werden. Hier darf die Statistik aufgrund der kleinen Fallzahlen weder im positiven noch im negativen Sinne überbewertet werden. Es sollte vielmehr Anlass zu Studien mit einem größeren Kollektiv geben, um die vorliegenden Tendenzen überprüfen zu können. Der Block des CTLA-4-Rezeptors führte zu einer Steigerung der CA125-spezifischen T-Zellresponse. Es fand sich jedoch kein Zusammenhang zu den gemessenen Treg-Frequenzen oder der CA125-spezifischen T-Zellresponse ohne einen CTLA-4-Rezeptor-Block. Bei der Auswertung der Effektor-T-Zellen wurde gezeigt, dass Patientinnen, die schon vor der Vakzinierung eine hohe CD8+ Effektor T-Zellen / CD4+FoxP3+ Treg -ratio hatten, sich im weiteren Verlauf zu mindestens einem Zeitpunkt eine Response entwickelt hat. Aus den vorliegenden Ergebnissen lässt sich folgern, dass die CTLA-4-abhängige Suppression nicht Treg-abhängig zu sein scheint. Für die Entwicklung einer CA125-spezifischen T-Zellresponse scheint vielmehr das Verhältnis zwischen Effektor-T-Zellen und regulatorischer T-Zellen entscheidend zu sein und nicht die Frequenz der regulatorischen T-Zellen alleine. Die Ergebnisse deuten darauf hin, dass die immunologische Wirksamkeit von Abagovomab durch immunsuppressive Mechanismen bei einzelnen Patienten gehemmt werden könnte. Bei diesen wäre in Zukunft möglicherweise eine Kombinationstherapie zwischen einer Immunisierung einerseits und einer Blockade der immunsuppressiven Mechanismen anderseits, eine therapeutische Option zur Verbesserung des Outcomes.

Ovarian cancer remains the leading cause of death due to gynecologic malignancies. Most patients present with advanced disease at the time of diagnosis. Although many have a good initial response to surgical debulking and platinum-based chemotherapy, relapse is common, with the eventual development of chemotherapy resistance. Innovative treatments are needed in the remission setting to prolong the disease-free interval or prevent recurrence. Abagovomab is a murine monoclonal anti-idiotypic antibody (molecular wieght: 165–175 kDa) that functionally imitates the tumor-associated antigen, CA-125. It has been shown to be well tolerated and to induce a sustained immune response in initial Phase I and II clinical trials. An ongoing, double-blind, placebo-controlled, multicenter, Phase III trial (MIMOSA) completed its double-blind period in December 2010 and will compare abagovomab maintenance therapy to placebo, which will definitively determine the efficacy of this immunotherapeutic approach in patients with ovarian cancer.

Ovarian cancer (OC) is the fifth most common cancer in women. Unfortunately, more than 70% of cases are detected at an advanced stage with a risk of recurrence, after front line therapy, of over 75%. The need for new therapeutic strategies is extremely high.The development status and the possible role of specific immunotherapy of abagovomab are discussed in the context of the possible therapeutic options for maintenance therapy in advanced OC. An overview of abagovomab, generation and mechanism of action, Phase I/II results and the status of the Phase II/III ongoing trial is given.Abagovomab stimulates the humoral immune response and the cell-mediated immune response in the studies conducted to date. In the proof of concept (POC) study abagovomab prolonged overall survival in those OC recurrent patients who showed an immune response. Abagovomab has an excellent safety and tolerability profile. These characteristics make abagovomab an optimal candidate for a maintenance treatment for OC patients after frontline therapy. The final results of the Phase II/III pivotal study evaluating abagovomab in this setting will be available in the first half of 2011.

Ovarian cancer has the highest mortality rate among gynaecological tumours despite the fact that the majority of patients with advanced disease achieve complete remission after first-line surgery and chemotherapy. Unfortunately, disease recurrence occurs in the majority of patients and second-line treatments are not curative. Clearly, the persistence of dormant and drug-resistant cells after front-line treatments results in the inability to cure the disease. The identification of cancer-initiating cells or cancer stem cells as key players in the development of recurrence has opened up a novel field of research aimed at identifying additional innovative therapeutic approaches. Strategies of maintenance therapy to extend the survival of patients have been studied, but to date no overall survival benefit has been detected. Currently, numerous clinical trials have just been completed or are ongoing involving patients achieving a complete clinical response after first-line chemotherapy in order to evaluate the efficacy of different therapeutic approaches in terms of disease-free survival and overall survival. At the 2010 ASCO meeting, the first positive results of a phase III clinical trial in this setting were presented: bevacizumab (15 mg/kg i.v. every 21 days) added to first-line chemotherapy and continued for an additional 15 cycles was found to prolong progression-free survival of 3.8 months in comparison to 6 cycles of chemotherapy alone or only 6 cycles of chemotherapy plus bevacizumab. In addition, positive results were announced for a second phase III trial testing bevacizumab in the same setting, but at half dose. The final assessment of the overall clinical benefit and the approval of bevacizumab in maintenance therapy by regulatory agencies is expected to be positive, as are the final results of abagovomab phase III trial MIMOSA, another antibody-based therapy tested as a maintenance treatment for advanced ovarian cancer patients. Encouraging preliminary results confirming the safety profile and the immunogenic activity of abagovomab were presented at the last ASCO meeting. The final results are expected to be released in the first half of 2011.

The results of several clinical trials have clearly demonstrated the potential of the anti-idiotype (anti-Id) vaccine abagovomab to induce cancer antigen 125 (CA-125)-specific immunity in ovarian cancer patients. Because of the central role of regulatory T cells (Tregs) in tumor immunology, we analyzed the frequency and suppressive activity of CD25 + FoxP3 + Tregs in 16 patients treated with abagovomab. During vaccination, mean frequencies of peripheral Treg with a CD4 + CD25 + FoxP3 + CD127 − phenotype were enhanced but returned to baseline levels in the follow-up phase. Despite increasing Treg counts, the suppressive activity of Tregs was diminished in a subset of patients treated with abagovomab. Reduced Treg activity was associated with increasing polyclonal and CA-125–specific T-cell proliferation in these patients. Interestingly, CA-125–specific T-cell activation could not be further improved by Treg depletion in vitro , as CA-125 induced a suppressive CD4 + CD25 + FoxP3 + CD127 − T cell subset derived from the originally Treg-depleted T-cell fraction. These CA-125–induced Tregs (iTregs) efficiently blocked polyclonal and tumor-specific T-cell activation. Further elimination of iTregs resulted in detectable CA-125–specific T-cell responses in a subset of patients. Based on our results, the suppressive potential rather than the frequency of natural and CA-125–induced Tregs is an important issues to consider for refinement of current anti-Id vaccination.

Ovarian cancer is the fifth most common malignancy with approximately 22,000 newly diagnosed cases each year in the USA. Standard of care after cytoreductive surgery is the application of carboplatin and paclitaxel. The newly developed anti-idiotypic monoclonal antibody abagovomab demonstrated promising results in Phase I/II trials. This new type of drug is currently being tested in a Phase II/III trial in ovarian cancer patients with a complete response after standard first-line chemotherapy. Activating the cancer hosts immune system is a new strategy that is worth being pursued in the fight against ovarian cancer.

LBA5002 Background: Abagovomab, a murine monoclonal anti-idiotypic antibody directed against CA125, has been shown to induce an active immune response against CA125 tumor-associated antigen in advanced ovarian cancer patients. Methods: Abagovomab (A) has been tested in a randomized (2:1) double-blind, placebo (P) controlled, multicenter phase II/III trial in patients with FIGO stage III/IV ovarian cancer after complete response to platinum-taxane first-line chemotherapy. A (2 mg/1 ml) or P was given subcutaneously every 2 weeks for 6 weeks (induction phase); then every 4 weeks (maintenance phase) until recurrence, or up to 21 months after the last patient had been randomized. Primary endpoint is progression-free survival (PFS); secondary endpoints are OS and immunological response. An estimated 870 patients, with a mean follow-up of 18 months, were needed to observe at least 535 recurrences, which provides a power >90% in rejecting the null hypothesis of equality between A and P on PFS according to a hazard ratio (HR) of 1.33, in which median P PFS time is 18 months, significance level (a) 5% (two-sided), and the overall dropout rate 10%. Primary analysis was run on PFS in the ITT population. The design included a prospective stratification in randomization for the following prognostic factors: FIGO stage (III-IV); tumor size after debulking (residual tumor 1 cm); and CA125 serum level after the third cycle (35 U/ml). The Cox proportional hazards model was used for adjusting the primary analysis. Results: 888 patients were enrolled by December 2008, 593 in A arm and 295 in P arm. The median follow-up was 28.1 months and the mean number treatment administrations was 18. Baseline characteristics were balanced between arms. Overall tolerability profile was consistent with previous A studies. Median (95% CI) PFS was 13.24 (10.612-13.602) months for A arm and 13.21 (10.612-16.000) months for P arm; HR=1.099 (0.919-1.315); p=0.301. Conclusions: Treatment with A did not translate into a prolonged PFS.

5036 Background: Phase I/II data demonstrated that abagovomab, a murine monoclonal anti-idiotypic antibody against CA125, induces an active immune response against CA125 tumor-associated antigen (T...

To the Editor: In their article, Sabbatini et al. ([1][1]) describe the phase I data of abagovomab, a murine anti-idiotype antibody to the CA125-specific monoclonal antibody OC125. In their Introduction, they compare abagovomab's mechanism of action to oregovomab's, a murine Ab1 antibody to CA125.